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Long-Acting HIV Drugs for Maintenance and PrEP

Long-acting injectable drug formulations that can last for a month or more may one day offer a more convenient option for HIV maintenance therapy and a way to ensure better adherence to pre-exposure prophylaxis (PrEP).

Long-Acting Maintenance Treatment

One-pill-once-daily HIV regimens are a major advance over the handfuls of pills required in the early days of combination antiretroviral therapy (ART), but an injection taken once a month or even once a quarter could become an even more convenient maintenance option for people with well-controlled HIV.

David Margolis at CROI 2014 (photo: Liz Highleyman)

David Margolis presented results from LATTE, the Long-Acting Antiretroviral Treatment Enabling study (abstract 91LB). LATTE tested a combination of two oral antiretroviral drugs, the non-nucleoside reverse transcriptase inhibitor rilpivirine (Edurant, also in the Complera coformulation) and the new integrase inhibitor GSK1265744 (or GSK744 for sort).

Although this study used daily pills to see if the combination is safe and effective as maintenance therapy, both drugs are being developed as long-acting formulations. A study presented at the International AIDS Society conference last summer showed that long-acting nanosuspension formulations of the two drugs achieved adequate blood levels and appeared safe in HIV-negative volunteers.

LATTE included 243 previously untreated participants. Almost all were men, two-thirds were white, the median age was about 33 years, the median CD4 T-cell count was approximately 415 cells/mm3, and 16% had a high baseline viral load (>100,000 copies/mL).

During the induction phase, participants were randomly assigned to received a standard ART regimen consisting of one of three daily oral doses of GSK744 (10, 30, or 60 mg), or else efavirenz, in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), either tenofovir/emtricitabine (the drugs in Truvada) or abacavir/lamivudine (the drugs in Epzicom).

The rationale for this protocol is that past research indicates that GSK744 and rilpivirine do not work as well for people starting treatment with a high viral load. Therefore, the idea is to bring viral load down using a standard three-drug regimen, then switch to a simplified two-drug maintenance regimen once the virus is suppressed.

At 24 weeks, 87% of participants taking GSK744 (all doses combined) plus two NRTIs achieved undetectable viral load, as did 74% of those taking efavirenz plus two NRTIs. There was no significant difference in response rates for the three GSK744 doses. Of the 160 people who switched from NRTIs to rilpivirine, 93% maintained viral suppression at 48 weeks, as did 94% of people who stayed on efavirenz and two NRTIs.

GSK744 was generally safe and well tolerated. Serious adverse events were uncommon in all treatment arms. People taking GSK744 were less likely than efavirenz recipients to experience neuropsychiatric side effects such as dizziness or abnormal dreams, and were less likely to drop out due to adverse events (4% vs 13%). Headache, however, was more common with GSK744.

Investigators are now working on a trial that will test long-acting injectable formulations of GSK744 and rilpivirine given at four- and eight-week intervals, Margolis said at a CROI press conference.

The issue with long-acting injectables is how to handle the “tail,” he explained. When someone discontinues long-lasting treatment, they will continue to have relatively high drug concentrations for a while. If these drugs are present in the body without a fully suppressive ART regimen, resistance could develop. LATTE offers reassurance that GSK744 and rilpivirine together can maintain viral suppression, but more study is needed to see how drug levels drop off at the end of the effective period.

GSK744 for PrEP

Two other studies looked at an injectable formulation of GSK744 given to macaque monkeys as PrEP prior to vaginal exposure to a HIV-like hybrid virus known as SHIV.

Large studies including the iPrEx trial showed that daily oral tenofovir (Viread) taken as PrEP could reduce the risk of becoming infected with HIV by more than 90%, but it only works if people achieve good adherence and maintain adequate drug levels in their body. For some people this could be easier with a long-acting injection—just as some women prefer Depo Provera injections every three months to daily birth control pills.

In the first study, Chasity Andrews from Aaron Diamond Research Institute and colleagues tested single injections of GSK744 to see how long it would provide protection against periodic high-dose vaginal exposures to SHIV (abstract 941). They found that while all four untreated female monkeys became infected after a single exposure, six of the eight treated monkeys remained uninfected through week 24.

Andrews previously reported findings from a similar study looking at male macaques given weekly rectal exposures to low-dose SHIV. Here, too, they found that untreated monkeys became infected after one to seven exposures, compared with six to 17 exposures for monkeys treated with GSK744.

In another study (abstract 40LB), Gerardo Garcia-Lerma from the Centers for Disease Control and Prevention and colleagues administered three monthly injections of GSK744 to six monkeys, which were exposed twice weekly to low amounts of SHIV—more closely resembling a typical pattern of sexual exposure. Again, none of the six treated monkeys became infected over the 12-week study, while all six untreated animals were infected, usually within five weeks.

The researchers noted that GSK744 drug levels in the monkeys were lower in rectal secretions compared with blood plasma, and lower still in vaginal secretions. However, they expect that protective levels can be achieved in humans using monthly or quarterly injections.

The HIV Prevention Trials Network will start a Phase 2a study this spring—HPTN 077—looking at the safety, tolerability, and acceptability of injectable GSK1265744 for PrEP in men and women. San Francisco will be one of the trial sites.